Neurology

Lin, Chun Chieh PhD, MBA; Callaghan, Brian C. MD, MS; Burke, James F. MD, MS; Skolarus, Lesli E. MD, MS; Hill, Chloe E. MD, MS; Magliocco, Brandon MS; Esper, Gregory J. MD, MBA; Kerber, Kevin A. MD, MS

doi : 10.1212/WNL.0000000000011276

pg. e309-e321

AB Objective: To describe geographic variation in neurologist density, neurologic conditions, and neurologist involvement in neurologic care. Methods: We used 20% 2015 Medicare data to summarize variation by Hospital Referral Region (HRR). Neurologic care was defined as office-based evaluation/management visits with a primary diagnosis of a neurologic condition. Results: Mean density of neurologists varied nearly 4-fold from the lowest to the highest density quintile (9.7 [95% confidence interval (CI) 9.2-10.2] vs 43.1 [95% CI 37.6-48.5] per 100,000 Medicare beneficiaries). The mean prevalence of patients with neurologic conditions did not substantially differ across neurologist density quintile regions (293 vs 311 per 1,000 beneficiaries in the lowest vs highest quintiles, respectively). Of patients with a neurologic condition, 23.5% were seen by a neurologist, ranging from 20.6% in the lowest quintile regions to 27.0% in the highest quintile regions (6.4% absolute difference). Most of the difference comprised dementia, pain, and stroke conditions seen by neurologists. In contrast, very little of the difference comprised Parkinson disease and multiple sclerosis, both of which had a very high proportion (>80%) of neurologist involvement even in the lowest quintile regions. Conclusions: The supply of neurologists varies substantially by region, but the prevalence of neurologic conditions does not. As neurologist supply increases, access to neurologist care for certain neurologic conditions (dementia, pain, and stroke) increases much more than for others (Parkinson disease and multiple sclerosis). These data provide insight for policy makers when considering strategies in matching the demand for neurologic care with the appropriate supply of neurologists. (C) 2021 American Academy of Neurology

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Increasing Out-of-Pocket Costs for Neurologic Care for Privately Insured Patients.

Hill, Chloe E. MD, MS; Reynolds, Evan L. PhD; Burke, James F. MD, MS; Banerjee, Mousumi PhD; Kerber, Kevin A. MD, MS; Magliocco, Brandon MS; Esper, Gregory J. MD, MBA; Skolarus, Lesli E. MD, MS; Callaghan, Brian C. MD, MS

doi : 10.1212/WNL.0000000000011278

pg. e322-e332

AB Objective: To measure the out-of-pocket (OOP) costs of evaluation and management (E/M) services and common diagnostic testing for neurology patients. Methods: Using a large, privately insured health care claims database, we identified patients with a neurologic visit or diagnostic test from 2001 to 2016 and assessed inflation-adjusted OOP costs for E/M visits, neuroimaging, and neurophysiologic testing. For each diagnostic service each year, we estimated the proportion of patients with OOP costs, the mean OOP cost, and the proportion of the total service cost paid OOP. We modeled OOP cost as a function of patient and insurance factors. Results: We identified 3,724,342 patients. The most frequent neurologic services were E/M visits (78.5%), EMG/nerve conduction studies (NCS) (7.7%), MRIs (5.3%), and EEGs (4.5%). Annually, 86.5%-95.2% of patients paid OOP costs for E/M visits and 23.1%-69.5% for diagnostic tests. For patients paying any OOP cost, the mean OOP cost increased over time, most substantially for EEG, MRI, and E/M. OOP costs varied considerably; for an MRI in 2016, the 50th percentile paid $103.10 and the 95th percentile paid $875.40. The proportion of total service cost paid OOP increased. High deductible health plan (HDHP) enrollment was associated with higher OOP costs for MRI, EMG/NCS, and EEG. Conclusion: An increasing number of patients pay OOP for neurologic diagnostic services. These costs are rising and vary greatly across patients and tests. The cost sharing burden is particularly high for the growing population with HDHPs. In this setting, neurologic evaluation might result in financial hardship for patients. (C) 2021 American Academy of Neurology

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Association of White Matter Lesions and Outcome After Endovascular Stroke Treatment.

Luijten, Sven P.R. MD; Bos, Daniel MD, PhD; Compagne, Kars C.J. BSc; Wolff, Lennard MD; Majoie, Charles B.L.M. MD, PhD; Roos, Yvo B.W.E.M. MD, PhD; van Zwam, Wim H. MD, PhD; van Oostenbrugge, Robert J. MD, PhD; Dippel, Diederik W.J. MD, PhD; van der Lugt, Aad MD, PhD; van Es, Adriaan C.G.M. MD, PhD; for the MR CLEAN trial investigators; for the MR CLEAN trial investigators; Dippel, Diederik MD, PhD; Lugt, Aad van de MD, PhD; Majoie, Charles B.L.M MD, PhD; Roos, Yvo B.W.E.M MD, PhD; van Oostenbrugge, Robert MD, PhD; van Zwam, Wim H MD, PhD; Berkhemer, Olvert A MD, PhD; Fransen, Puck S.S MD, PhD; Beumer, Debbie MD, PhD; van den Berg, Lucie A MD, PhD; Schonewille, Wouter J MD, PhD; Vos, Jan Albert MD, PhD; Nederkoorn, Paul J MD, PhD; Werme, Marieke J.H MD, PhD; van Walderveen, Marianne A.A MD, PhD; Staals, Julie MD, PhD; Hofmeijer, Jeanette MD, PhD; van Oostayen, Jacques A MD, PhD; Lycklama a Nijeholt, Geert J MD, PhD; Boiten, Jelis MD, PhD; Brouwer, Patrick A MD, PhD; Emmer, Bart J MD, PhD; de Bruijn, Sebastiaan F MD, PhD; van Dijk, Lukas C MD; Kappelle, L.Jaap MD, PhD; Lo, Rob H MD, PhD; van Dijk, Ewoud J MD, PhD; de Vries, Joost MD, PhD; de Kort, Paul L.M MD, PhD; van den Berg, Jan S.P MD, PhD; van Rooij, Willem Jan. J MD, PhD; van Hasselt, Boudewijn A.A.M MD, PhD; Aerden, Leo A.M MD, PhD; Dallinga, Rene J MD, PhD; Visser, Marieke C MD; Bot, Joseph C.J MD, PhD; Vroomen, Patrick C MD, PhD; Eshghi, Omid MD, PhD; Schreuder, Tobien H.C.M.L MD, PhD; Heijboer, Roel J.J MD, PhD; Keizer, Koos MD, PhD; Tielbeek, Alexander V MD, PhD; den Hertog, Heleen M MD, PhD; Gerrits, Dick G MD; van den Berg-Vos, Renske M MD, PhD; Karas, Giorgos B MD, PhD; Marquering, Henk A PhD; Beenen, Ludo F MD, PhD; Sprengers, Marieke E.S MD, PhD; Jenniskens, Sjoerd F.M MD, PhD; Albert J. Yoo, Gerson MD; Koudstaal, Peter J MD, PhD; Flach, Zwenneke H MD; Steyerberg, Ewout W PhD; Lingsma, Hester F PhD

doi : 10.1212/WNL.0000000000010994

pg. e333-e342

AB Objective: To investigate the association between white matter lesions (WML) and functional outcome in patients with acute ischemic stroke (AIS) and the modification of the effect of endovascular treatment (EVT) by WML. Methods: We used data from the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) trial and assessed severity of WML on baseline noncontrast CT imaging (NCCT; n = 473) according to the Van Swieten Scale. Poststroke functional outcome was assessed with the modified Rankin Scale. We investigated the association of WML with functional outcome using ordinal logistic regression models adjusted for age, sex, and other relevant cardiovascular and prognostic risk factors. In addition, an interaction term between treatment allocation and WML severity was used to assess treatment effect modification by WML. Results: We found an independent negative association between more severe WML and functional outcome (adjusted common odds ratio [acOR] 0.77 [95% confidence interval (CI) 0.66-0.90]). Patients with absent to moderate WML had similar benefit of EVT on functional outcome (acOR 1.93 [95% CI 1.31-2.84]) as patients with severe WML (acOR 1.95 [95% CI 0.90-4.20]). No treatment effect modification of WML was found (p for interaction = 0.85). Conclusions: WML are associated with poor functional outcome after AIS, but do not modify the effect of EVT. Classification of Evidence: Prognostic accuracy. This study provides Class II evidence that for patients with AIS, the presence of WML on baseline NCCT is associated with worse functional outcomes. (C) 2021 American Academy of Neurology

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Clinical Diffusion Mismatch to Select Pediatric Patients for Embolectomy 6 to 24 Hours After Stroke: An Analysis of the Save ChildS Study.

Sporns, Peter B. MD, MHBA; Psychogios, Marios-Nikos MD; Straeter, Ronald MD; Hanning, Uta MD, MHBA; Minnerup, Jens MD; Chapot, Rene MD; Henkes, Hans MD; Henkes, Elina MD; Grams, Astrid MD; Dorn, Franziska MD; Nikoubashman, Omid MD; Wiesmann, Martin MD; Bier, Georg MD; Weber, Anushe MD; Broocks, Gabriel MD; Fiehler, Jens MD; Brehm, Alex MD; Kaiser, Daniel MD; Yilmaz, Umut MD; Morotti, Andrea MD; Marik, Wolfgang MD; Nolz, Richard MD; Jensen-Kondering, Ulf MD; Braun, Michael MD; Schob, Stefan MD; Beuing, Oliver MD; Goetz, Friedrich MD; Trenkler, Johannes MD; Turowski, Bernd MD; Mohlenbruch, Markus MD; Wendl, Christina MD; Schramm, Peter MD; Musolino, Patricia L. PhD; Lee, Sarah MD; Schlamann, Marc MD; Radbruch, Alexander MD, JD; Karch, Andre MD, PhD; Rubsamen, Nicole PhD; Wildgruber, Moritz MD, PhD *; Kemmling, Andre MD, MHBA *; the Save ChildS Investigators; the Save ChildS Investigators; Sporns, Peter B MD, MHBA; Psychogios, Marios-Nikos MD; Straeter, Ronald MD; Hanning, Uta MD, MHBA; Minnerup, Jens MD; Chapot, Rene MD; Henkes, Hans MD; Henkes, Elina MD, PhD; Grams, Astrid MD; Dorn, Franziska MD; Nikoubashman, Omid MD; Wiesmann, Martin MD; Bier, Georg MD; Weber, Anushe MD; Broocks, Gabriel MD; Fiehler, Jens MD; Brehm, Alex MD; Kaiser, Daniel MD; Yilmaz, Umut MD; Morotti, Andrea MD; Marik, Wolfgang MD; Nolz, Richard MD; Jensen- Kondering, Ulf MD; Braun, Michael MD; Schob, Stefan MD; Beuing, Oliver MD; Goetz, Friedrich MD; Trenkler, Johannes MD; Turowski, Bernd MD; ohlenbruch, Markus M MD; Wendl, Christina MD; Schramm, Peter MD; Musolino, Patricia L MD; Lee, Sarah MD; Schlamann, Marc MD; Radbruch, Alexander MD; Karch, Andre MD; Rusamen, Nicole MD; Wildgruber, Moritz MD; Kemmling, Andre MD

doi : 10.1212/WNL.0000000000011107

pg. e343-e351

AB Objective: To determine whether thrombectomy is safe in children up to 24 hours after onset of symptoms when selected by mismatch between clinical deficit and infarct. Methods: A secondary analysis of the Save ChildS Study (January 2000-December 2018) was performed, including all pediatric patients (<18 years) diagnosed with arterial ischemic stroke who underwent endovascular recanalization at 27 European and United States stroke centers. Patients were included if they had a relevant mismatch between clinical deficit and infarct. Results: Twenty children with a median age of 10.5 (interquartile range [IQR] 7-14.6) years were included. Of those, 7 were male (35%), and median time from onset to thrombectomy was 9.8 (IQR 7.8-16.2) hours. Neurologic outcome improved from a median Pediatric NIH Stroke Scale score of 12.0 (IQR 8.8-20.3) at admission to 2.0 (IQR 1.2-6.8) at day 7. Median modified Rankin Scale (mRS) score was 1.0 (IQR 0-1.6) at 3 months and 0.0 (IQR 0-1.0) at 24 months. One patient developed transient peri-interventional vasospasm; no other complications were observed. A comparison of the mRS score to the mRS score in the DAWN and DEFUSE 3 trials revealed a higher proportion of good outcomes in the pediatric compared to the adult study population. Conclusions: Thrombectomy in pediatric ischemic stroke in an extended time window of up to 24 hours after onset of symptoms seems safe and neurologic outcomes are generally good if patients are selected by a mismatch between clinical deficit and infarct. Classification of Evidence: This study provides Class IV evidence that for children with acute ischemic stroke with a mismatch between clinical deficit and infarct size, thrombectomy is safe. (C) 2021 American Academy of Neurology

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Contribution of Ictal Source Imaging for Localizing Seizure Onset Zone in Patients With Focal Epilepsy.

Ye, Shuai MS *; Yang, Lin PhD *; Lu, Yunfeng PhD; Kucewicz, Michal T. PhD; Brinkmann, Benjamin PhD; Nelson, Cindy REEGT; Sohrabpour, Abbas PhD; Worrell, Gregory A. MD, PhD; He, Bin PhD

doi : 10.1212/WNL.0000000000011109

pg. e366-e375

AB Objective: To determine whether seizure onset zone (SOZ) can be localized accurately prior to surgical planning in patients with focal epilepsy, we performed noninvasive EEG recordings and source localization analyses on 39 patients. Methods: In 39 patients with focal epilepsy, we recorded and extracted 138 seizures and 1,325 interictal epileptic discharges using high-density EEG. We investigated a novel approach for directly imaging sources of seizures and interictal spikes from high-density EEG recordings, and rigorously validated it for noninvasive localization of SOZ determined from intracranial EEG findings and surgical resection volume. Conventional source imaging analyses were also performed for comparison. Results: Ictal source imaging showed a concordance rate of 95% when compared to intracranial EEG or resection results. The average distance from estimation to seizure onset (intracranial) electrodes is 1.35 cm in patients with concordant results, and 0.74 cm to surgical resection boundary in patients with successful surgery. About 41% of the patients were found to have multiple types of interictal activities; coincidentally, a lower concordance rate and a significantly worse performance in localizing SOZ were observed in these patients. Conclusion: Noninvasive ictal source imaging with high-density EEG recording can provide highly concordant results with clinical decisions obtained by invasive monitoring or confirmed by resective surgery. By means of direct seizure imaging using high-density scalp EEG recordings, the added value of ictal source imaging is particularly high in patients with complex interictal activity patterns, who may represent the most challenging cases with poor prognosis. (C) 2021 American Academy of Neurology

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Siponimod and Cognition in Secondary Progressive Multiple Sclerosis: EXPAND Secondary Analyses.

Benedict, Ralph H.B. PhD; Tomic, Davorka MD; Cree, Bruce A. MD; Fox, Robert MD; Giovannoni, Gavin MD; Bar-Or, Amit MD; Gold, Ralf MD; Vermersch, Patrick MD; Pohlmann, Harald MSc; Wright, Ian PhD; Karlsson, Goril MD; Dahlke, Frank MD; Wolf, Christian MD; Kappos, Ludwig MD

doi : 10.1212/WNL.0000000000011275

pg. e376-e386

AB Objective: To investigate the effects of siponimod on cognitive processing speed in patients with secondary progressive (SP) multiple sclerosis (MS), by means of a predefined exploratory and post hoc analysis of the Exploring the Efficacy and Safety of Siponimod in Patients With Secondary Progressive Multiple Sclerosis (EXPAND) study, a randomized controlled trial comparing siponimod and placebo. Methods: EXPAND was a double-blind, placebo-controlled phase 3 trial involving 1,651 patients with SPMS randomized (2:1) to either siponimod 2 mg/d or placebo. Cognitive function was assessed with the Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test (PASAT), and Brief Visuospatial Memory Test-Revised (BVMT-R) administered at baseline, 6-month intervals, and end of treatment. Results: Between-group differences in mean change from baseline in SDMT scores were significantly better in siponimod- vs placebo-treated patients at month 12 (difference 1.08 [95% confidence interval 0.23-1.94]; p = 0.0132), month 18 (1.23 [0.25-2.21); p = 0.0135), and month 24 (2.30 [1.11-3.50]; p = 0.0002). Siponimod-treated patients were at significantly lower risk for having a 4-point sustained decrease in SDMT score (hazard ratio [HR] 0.79 [0.65-0.96]; p = 0.0157), while their chance for having a 4-point sustained increase in SDMT score was higher (HR 1.28 [1.05-1.55]; p = 0.0131). PASAT and BVMT-R scores did not differ significantly between the 2 treatment groups (all p > 0.28). Conclusion: Siponimod had a significant benefit on SDMT in patients with SPMS. Siponimod-treated patients were at significantly lower risk for having a >=4-point decrease in SDMT score and had a significantly higher chance for having a >=4-point increase in SDMT score, a magnitude of change accepted as clinically meaningful. ClinicalTrials.gov Identifier: NCT01665144. Classification of Evidence: This study provides Class II evidence that, for patients with SPMS, siponimod had a significant benefit on cognitive processing speed. (C) 2021 American Academy of Neurology

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Comparison of Clinical Outcomes 1 and 5 Years Post-Injury Following Combat Concussion.

Mac Donald, Christine L. PhD; Barber, Jason MS; Patterson, Jana; Johnson, Ann M.; Parsey, Carolyn PhD; Scott, Beverly MD; Fann, Jesse R. MD, MPH; Temkin, Nancy R. PhD

doi : 10.1212/WNL.0000000000011089

pg. e387-e398

AB Objective: To compare 1-year and 5-year clinical outcomes in 2 groups of combat-deployed service members without brain injury to those of 2 groups with combat-related concussion to better understand long-term clinical outcome trajectories. Methods: This prospective, observational, longitudinal multicohort study examined 4 combat-deployed groups: controls without head injury with or without blast exposure and patients with combat concussion arising from blast or blunt trauma. One-year and 5-year clinical evaluations included identical batteries for neurobehavioral, psychiatric, and cognitive outcomes. A total of 347 participants completed both time points of evaluation. Cross-sectional and longitudinal comparisons were assessed. Overall group effect was modeled as a 4-category variable with rank regression adjusting for demographic factors using a 2-sided significance threshold of 0.05, with post hoc Tukey p values calculated for the pairwise comparisons. Results: Significant group differences in both combat concussion groups were identified cross-sectionally at 5-year follow-up compared to controls in neurobehavioral (Neurobehavioral Rating Scale-Revised [NRS]; Cohen d, -1.10 to -1.40, confidence intervals [CIs] [-0.82, -1.32] to [-0.97, -1.83] by group) and psychiatric domains (Clinician-Administered PTSD Scale for DSM-IV [CAPS]; Cohen d, -0.91 to -1.19, CIs [-0.63, -1.19] to [-0.76, -1.62] by group) symptoms with minimal differences in cognitive performance. Both combat concussion groups also showed clinically significant decline from 1- to 5-year evaluation (66%-76% neurobehavioral NRS; 41%-54% psychiatric CAPS by group). Both control groups fared better but a subset also had clinically significant decline (37%-50% neurobehavioral NRS; 9%-25% psychiatric CAPS by group). Conclusions: There was an evolution, not resolution, of symptoms from 1- to 5-year evaluation, challenging the assumption that chronic stages of concussive injury are relatively stable. Even some of the combat-deployed controls worsened. The evidence supports new considerations for chronic trajectories of concussion outcome in combat-deployed service members. (C) 2021 American Academy of Neurology

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Phenylalanine Effects on Brain Function in Adult Phenylketonuria.

Pilotto, Andrea MD; Zipser, Carl M. MD; Leks, Edytha MD; Haas, Dorothea MD; Gramer, Gwendolyn MD; Freisinger, Peter MD; Schaeffer, Eva MD; Liepelt-Scarfone, Inga PhD; Brockmann, Kathrin MD; Maetzler, Walter MD; Schulte, Claudia Bio; Deuschle, Christian; Hauser, Ann Kathrin; Hoffmann, Georg F. MD; Scheffler, Klaus MD; van Spronsen, Francjan J. MD; Padovani, Alessandro MD, PhD; Trefz, Friedrich MD; Berg, Daniela MD

doi : 10.1212/WNL.0000000000011088

pg. e399-e411

AB Objective: To evaluate the relationship between circulating phenylalanine and brain function as well as neuropsychiatric symptoms in adults with phenylketonuria. Methods: In this prospective cross-sectional study, early-treated patients with phenylketonuria older than 30 years and age- and sex-matched controls were included. Extensive neurologic evaluation, neuropsychological and behavioral testing, sensory and motor evoked potentials, and MRI were performed. CSF concentrations of neurodegenerative markers were evaluated in addition in a subset of 10 patients. Results: Nineteen patients with phenylketonuria (median age 41 years) with different phenylalanine levels (median 873 [mu]mol/L) entered the study. They showed higher prevalence of neurologic symptoms, cognitive and behavioral abnormalities, autonomic dysfunction, alterations in neurophysiologic measures, and atrophy in putamen and right thalamus compared to controls. In CSF, patients with phenylketonuria exhibited higher [beta]-amyloid 1-42 (p = 0.003), total tau (p < 0.001), and phosphorylated tau (p = 0.032) levels compared to controls. Plasma phenylalanine levels highly correlated with the number of failed neuropsychological tests (r = 0.64, p = 0.003), neuropsychiatric symptoms (r = 0.73, p < 001), motor evoked potential latency (r = 0.48, p = 0.030), and parietal lobe atrophy. Conclusions: Our study provides strong evidence for a correlation between phenylalanine levels and clinical, neuropsychological, neurophysiologic, biochemical, and imaging alterations in adult patients with phenylketonuria. (C) 2021 American Academy of Neurology

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Neurofilament Light Chain as a Biomarker of Hereditary Transthyretin-Mediated Amyloidosis.

Ticau, Simina PhD *; Sridharan, Gautham V. PhD *; Tsour, Shira MS; Cantley, William L. PhD; Chan, Amy PhD; Gilbert, Jason A. MS; Erbe, David PhD; Aldinc, Emre MD; Reilly, Mary M. MD; Adams, David MD; Polydefkis, Michael MD; Fitzgerald, Kevin PhD; Vaishnaw, Akshay MD; Nioi, Paul PhD

doi : 10.1212/WNL.0000000000011090

pg. e412-e422

AB Objective: To identify changes in the proteome associated with onset and progression of hereditary transthyretin-mediated (hATTR) amyloidosis, also known as ATTRv amyloidosis, we performed an observational, case-controlled study that compared proteomes of patients with ATTRv amyloidosis and healthy controls. Methods: Plasma levels of >1,000 proteins were measured in patients with ATTRv amyloidosis with polyneuropathy who received either placebo or patisiran in a Phase 3 study of patisiran (APOLLO), and in healthy controls. The effect of patisiran on the time profile of each protein was determined by linear mixed model at 0, 9, and 18 months. Neurofilament light chain (NfL) was further assessed with an orthogonal quantitative approach. Results: Levels of 66 proteins were significantly changed with patisiran vs placebo, with NfL change most significant (p < 10-20). Analysis of changes in protein levels demonstrated that the proteome of patients treated with patisiran trended toward that of healthy controls at 18 months. Healthy controls' NfL levels were 4-fold lower than in patients with ATTRv amyloidosis with polyneuropathy (16.3 pg/mL vs 69.4 pg/mL, effect -53.1 pg/mL [95% confidence interval -60.5 to -45.9]). NfL levels at 18 months increased with placebo (99.5 pg/mL vs 63.2 pg/mL, effect 36.3 pg/mL [16.5-56.1]) and decreased with patisiran treatment (48.8 pg/mL vs 72.1 pg/mL, effect -23.3 pg/mL [-33.4 to -13.1]) from baseline. At 18 months, improvement in modified Neuropathy Impairment Score +7 score after patisiran treatment significantly correlated with reduced NfL (R = 0.43 [0.29-0.55]). Conclusions: Findings suggest that NfL may serve as a biomarker of nerve damage and polyneuropathy in ATTRv amyloidosis, enable earlier diagnosis of patients with ATTRv amyloidosis, and facilitate monitoring of disease progression. Classification of Evidence: This study provides Class III evidence that NfL levels may enable earlier diagnosis of polyneuropathy in patients with ATTRv amyloidosis and facilitate monitoring of disease progression. (C) 2021 American Academy of Neurology

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Clinical, Genetic, and Disability Profile of Pediatric Distal Hereditary Motor Neuropathy.

Argente-Escrig, Herminia MD; Burns, Joshua PhD; Donlevy, Gabrielle MSc; Frasquet, Marina MD; Cornett, Kayla PhD; Sevilla, Teresa MD, PhD; Menezes, Manoj P. MD, PhD

doi : 10.1212/WNL.0000000000011054

pg. e423-e432

AB Objective: To describe the clinical, genetic, and disability profile of pediatric distal hereditary motor neuropathy (dHMN) and to determine the utility of an outcome measure validated for children with Charcot-Marie-Tooth disease (CMT) in assessing disability in this cohort. Methods: We reviewed the clinical, neurophysiologic, and disability data on individuals with dHMN, evaluated before the age of 20 years, at 2 tertiary neuromuscular clinics in Australia and Spain. Disability was assessed annually with the CMT Pediatric Scale (CMTPedS) in a subset of individuals. Results: Twenty-two children (13 female) from 19 families were included. Fourteen individuals were symptomatic in the first year of life. Intellectual disability was present in 6 individuals; upper motor neuron signs were seen in 8. Pathogenic variants were found in 9 families, more frequently in BICD2 (BICD2-4, DYNC1H1-2, MFN2-2, GARS-1). A novel pathogenic variant in the GARS gene was detected and characterized phenotypically. Disability was moderate on the CMTPedS (mean [SD] 18.2 [6.3], n = 16), with balance and long jump being the most affected and sensation items and grip strength the least affected. Over 1 year, the CMTPedS total score deteriorated, on average 1.5 points (SD 3.7) or 9% (n = 12), with significant variability in the rate of progression within the cohort. Conclusions: The genetic profile of pediatric dHMN is different from that identified in adult cohorts. This study has identified distinct functional limitations for the CMTPedS in children and adolescents with dHMN. (C) 2021 American Academy of Neurology

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Scan-Negative Cauda Equina Syndrome: A Prospective Cohort Study.

Hoeritzauer, Ingrid MRCP; Carson, Alan FRCPsych; Statham, Patrick FRCS; Panicker, Jalesh N. FRCP; Granitsiotis, Voula MRCS; Eugenicos, Maria FRCP, PhD; Summers, David FRCP; Demetriades, Andreas K. FRCS; Stone, Jon FRCP, PhD

doi : 10.1212/WNL.0000000000011154

pg. e433-e447

AB Objective: To describe clinical features relevant to diagnosis, mechanism, and etiology in patients with "scan-negative" cauda equina syndrome (CES). Methods: We carried out a prospective study of consecutive patients presenting with the clinical features of CES to a regional neurosurgery center comprising semi-structured interview and questionnaires investigating presenting symptoms, neurologic examination, psychiatric and functional disorder comorbidity, bladder/bowel/sexual function, distress, and disability. Results: A total of 198 patients presented consecutively over 28 months. A total of 47 were diagnosed with scan-positive CES (mean age 48 years, 43% female). A total of 76 mixed category patients had nerve root compression/displacement without CES compression (mean age 46 years, 71% female) and 61 patients had scan-negative CES (mean age 40 years, 77% female). An alternative neurologic cause of CES emerged in 14/198 patients during admission and 4/151 patients with mean duration 25 months follow-up. Patients with scan-negative CES had more positive clinical signs of a functional neurologic disorder (11% scan-positive CES vs 34% mixed and 68% scan-negative, p < 0.0001), were more likely to describe their current back pain as worst ever (41% vs 46% and 70%, p = 0.005), and were more likely to have symptoms of a panic attack at onset (37% vs 57% and 70%, p = 0.001). Patients with scan-positive CES were more likely to have reduced/absent bilateral ankle jerks (78% vs 30% and 12%, p < 0.0001). There was no significant difference between groups in the frequency of reduced anal tone and urinary retention. Conclusion: The first well-phenotyped, prospective study of scan-negative CES supports a model in which acute pain, medication, and mechanisms overlapping with functional neurologic disorders may be relevant. (C) 2021 American Academy of Neurology

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Pathologic Features of Anti-Mi-2 Dermatomyositis.

Tanboon, Jantima MD; Inoue, Michio MD; Hirakawa, Shinya PhD; Tachimori, Hisateru PhD; Hayashi, Shinichiro PhD; Noguchi, Satoru PhD; Suzuki, Shigeaki MD, PhD; Okiyama, Naoko MD, PhD; Fujimoto, Manabu MD, PhD; Nishino, Ichizo MD, PhD

doi : 10.1212/WNL.0000000000011269

pg. e448-e459

AB Objective: To identify the characteristic pathologic features of dermatomyositis (DM) associated with anti-Mi-2 autoantibodies (anti-Mi-2 DM). Methods: We reviewed 188 muscle biopsies from patients (1) pathologically diagnosed with DM through the sarcoplasmic expression for the myxovirus-resistant protein A and (2) serologically positive for 1 of 5 DM-specific autoantibodies (DMSAs) (anti-Mi-2, n = 30; other DMSAs, n = 152) or negative for all 5 DMSAs (n = 6). We then compared the histopathologic and immunohistochemical features of patients with anti-Mi-2 DM to those with non-Mi-2 DM and patients with anti-synthetase syndrome (ASS) (n = 212) using the t test, Fisher exact test, and a logistic regression model. Results: Patients with anti-Mi-2 DM showed significantly higher severity scores in muscle fiber and inflammatory domains than non-Mi-2 DM patients. The presence of perifascicular necrosis, increased perimysial alkaline phosphatase activity, and sarcolemmal membrane attack complex deposition was more frequent in patients with anti-Mi-2 DM (p < 0.01). After Bonferroni correction, there were no significant differences in the percentages of the features mentioned above between the patients with anti-Mi-2 DM and those with ASS (p > 0.01). Conclusion: Perifascicular necrosis and perimysial pathology, features previously reported in ASS, are common in patients with anti-Mi-2 DM. Our findings not only assist in differentiating anti-Mi-2 DM from other DM subtypes but also suggest the possibility of an overlapping mechanism between anti-Mi-2 DM and ASS. Classification of Evidence: This study provides Class II evidence that the muscle biopsies of DM patients with anti-Mi-2 autoantibodies are more likely to demonstrate higher severity scores in muscle fiber and inflammatory domains. (C) 2021 American Academy of Neurology

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Parkinson Disease Propagation Using MRI Biomarkers and Partial Least Squares Path Modeling.

Pyatigorskaya, Nadya MD, PhD *; Yahia-Cherif, Lydia PhD *; Valabregue, Romain PhD; Gaurav, Rahul MSc; Gargouri, Fatma PhD; Ewenczyk, Claire MD, PhD; Gallea, Cecile PhD; Fernandez-Vidal, Sara PhD; Arnulf, Isabelle MD, PhD; Vidailhet, Marie MD; Lehericy, Stephane MD, PhD

doi : 10.1212/WNL.0000000000011155

pg. e460-e471

AB Objectives: The classic Braak neuropathologic staging model in Parkinson disease (PD) suggests that brain lesions progress from the medulla oblongata to the cortex. An alternative model in which neurodegeneration first occurs in the cortex has also been proposed. These 2 models may correspond to different patient phenotypes. To test these 2 models and to investigate whether they were influenced by the presence of REM sleep behavior disorder (RBD), we used multimodal MRI and partial least squares path modeling (PLS-PM) assuming that patients with RBD followed distinct neurodegeneration pattern. Methods: Fifty-four patients with PD (34 with RBD) and 25 healthy volunteers were scanned with T1-weighted, diffusion tensor, and neuromelanin-sensitive imaging. Volume, signal, and mean, axial, and radial diffusivities were calculated in brainstem, basal forebrain, and cortical regions. PLS-PM, estimating a network of causal relationships between blocks of variables, was used to build and test an analytical model based on Braak staging. The overall quality of the model was assessed with goodness of fit coefficient (Gof). Results: PLS-PM was run on patients with PD with RBD and without RBD separately. In PD with RBD, a brainstem-to-cortex model had significant Gof (0.71, p = 0.01), whereas a cortex-to-brainstem model did not. In contrast, in patients with PD without RBD, the brainstem-to-cortex model was not significant (Gof = 0.64, p = 0.27), and the cortex-to-brainstem model was highly significant (Gof = 0.72, p = 0.008). Conclusions: With the PLS-PM imaging-based model, the neurodegeneration pattern of patients with PD with RBD was consistent with the Braak brainstem-to-cortex model, whereas that of patients without RBD followed the cortex-to-brainstem model. (C) 2021 American Academy of Neurology

خرید پکیج و مشاهده آنلاین مقاله

What's Happening in Neurology(R).

doi : 10.1212/WNL.0000000000011281

pg. 107

خرید پکیج و مشاهده آنلاین مقاله

What's Happening in Neurology(R) Genetics.

doi : 10.1212/WNL.0000000000011282

pg. 108

خرید پکیج و مشاهده آنلاین مقاله

What's Happening in Innovations in Care Delivery.

doi : 10.1212/WNL.0000000000011283

pg. 109

خرید پکیج و مشاهده آنلاین مقاله

What is the Role of the Claustrum in Cortical Function and Neurologic Disease?.

Benarroch, Eduardo E. MD

doi : 10.1212/WNL.0000000000011280

pg. 110-113

خرید پکیج و مشاهده آنلاین مقاله

International Consensus Guidance for Management of Myasthenia Gravis: 2020 Update.

Narayanaswami, Pushpa MBBS, DM; Sanders, Donald B. MD; Wolfe, Gil MD; Benatar, Michael MD; Cea, Gabriel MD; Evoli, Amelia MD; Gilhus, Nils Erik MD; Illa, Isabel MD; Kuntz, Nancy L. MD; Massey, Janice MD; Melms, Arthur MD; Murai, Hiroyuki MD; Nicolle, Michael MD; Palace, Jacqueline MD; Richman, David MD; Verschuuren, Jan MD

doi : 10.1212/WNL.0000000000011124

pg. 114-122

AB Objective: To update the 2016 formal consensus-based guidance for the management of myasthenia gravis (MG) based on the latest evidence in the literature. Methods: In October 2013, the Myasthenia Gravis Foundation of America appointed a Task Force to develop treatment guidance for MG, and a panel of 15 international experts was convened. The RAND/UCLA appropriateness method was used to develop consensus recommendations pertaining to 7 treatment topics. In February 2019, the international panel was reconvened with the addition of one member to represent South America. All previous recommendations were reviewed for currency, and new consensus recommendations were developed on topics that required inclusion or updates based on the recent literature. Up to 3 rounds of anonymous e-mail votes were used to reach consensus, with modifications to recommendations between rounds based on the panel input. A simple majority vote (80% of panel members voting "yes") was used to approve minor changes in grammar and syntax to improve clarity. Results: The previous recommendations for thymectomy were updated. New recommendations were developed for the use of rituximab, eculizumab, and methotrexate as well as for the following topics: early immunosuppression in ocular MG and MG associated with immune checkpoint inhibitor treatment. Conclusion: This updated formal consensus guidance of international MG experts, based on new evidence, provides recommendations to clinicians caring for patients with MG worldwide. (C) 2021 American Academy of Neurology

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Penicillamine for Hypermanganesemia With Dystonia, Polycythemia, and Cirrhosis in 2 Sisters.

Dutta, Arpan MD; Majumdar, Ritwika MD; Dubey, Souvik MD, DM; Pandit, Alak MD, DM

doi : 10.1212/WNL.0000000000011296

pg. 123-125

خرید پکیج و مشاهده آنلاین مقاله

Bilateral Thalamic Lesions Associated With Atezolizumab-Induced Autoimmune Encephalitis.

Nishijima, Haruo MD, PhD; Suzuki, Chieko MD, PhD; Kon, Tomoya MD, PhD; Nakamura, Takashi MD; Tanaka, Hisashi MD, PhD; Sakamoto, Yui MD; Tomiyama, Masahiko MD, PhD

doi : 10.1212/WNL.0000000000011297

pg. 126-127

خرید پکیج و مشاهده آنلاین مقاله

Clinical Reasoning: A 33-Year-Old Patient With Left-Sided Hemiparesis and Anarthria.

Schowalter, Sean MD; Katz, Douglas I. MD; Lin, David J. MD

doi : 10.1212/WNL.0000000000010809

pg. 128-133

خرید پکیج و مشاهده آنلاین مقاله

Education Research: A Qualitative Study on Student Perceptions of Neurology and Psychiatry Clerkship Integration.

Mowchun, Justin J. MD, MScEd; Frew, Julia R. MD; Shoop, Glenda Hostetter PhD

doi : 10.1212/WNL.0000000000010842

pg. e472-e477

AB Objective: To explore student perceptions of the feasibility of neurology and psychiatry clerkship integration, including clinical education and competency evaluation, as there has been a call to improve undergraduate medical education integration of the disciplines to better develop physicians that can address nervous system disorders. Method: Via a constructivist grounded theory approach, we carried out 5 focus groups in 2016-2017 with 28 medical students who completed both independent clerkships. Investigator triangulation was used with iterative interpretation comparisons, and themes were identified using constant comparative analysis. Results: Three major themes arose: (1) combining the clerkships was not favorable as students need sufficient time to delve deeper into each discipline; (2) students did not observe an integrated clinical approach by faculty; (3) there is positive value to making links between neurology and psychiatry for effective patient care. Conclusions: Students emphasized the importance of making stronger links between the 2 disciplines for their learning and to improve patient care; however, they did not observe this clinical approach in the workplace. Students perceived that integration of neurology and psychiatry clerkships should occur via increased affinity of the complementary discipline by trainees and faculty in each specialty. (C) 2021 American Academy of Neurology

خرید پکیج و مشاهده آنلاین مقاله

Teaching NeuroImages: All Hemiparesis Are Not Contralateral.

Reddy, Y. Muralidhar DM (Neurology), ASN (Certification); Parida, Subhendu DM (Neuroradiology); Murthy, Jagarlapudi M.K. DM (Neurology), FAAN

doi : 10.1212/WNL.0000000000010755

pg. e478-e479

خرید پکیج و مشاهده آنلاین مقاله

Editors' Note: Safety and Efficacy of Dual Antiplatelet Pretreatment in Patients With Ischemic Stroke Treated With IV Thrombolysis: A Systematic Review and Meta-analysis.

Siegler, James E. III MD; Galetta, Steven MD

doi : 10.1212/WNL.0000000000011284

pg. 134

خرید پکیج و مشاهده آنلاین مقاله

Reader Response: Safety and Efficacy of Dual Antiplatelet Pretreatment in Patients With Ischemic Stroke Treated With IV Thrombolysis: A Systematic Review and Meta-analysis.

Xu, Weilin; Hu, Xin

doi : 10.1212/WNL.0000000000011290

pg. 134-135

خرید پکیج و مشاهده آنلاین مقاله

Author Response: Safety and Efficacy of Dual Antiplatelet Pretreatment in Patients With Ischemic Stroke Treated With IV Thrombolysis: A Systematic Review and Meta-analysis.

Katsanos, Aristeidis H.; Tsivgoulis, Georgios

doi : 10.1212/WNL.0000000000011291

pg. 135

خرید پکیج و مشاهده آنلاین مقاله

Editors' Note: Three-Month Modified Rankin Scale as a Determinant of 5-Year Cumulative Costs After Ischemic Stroke: An Analysis of 11,136 Patients in Korea.

Siegler, James E. III MD; Galetta, Steven MD

doi : 10.1212/WNL.0000000000011292

pg. 135-136

خرید پکیج و مشاهده آنلاین مقاله

Reader Response: Three-Month Modified Rankin Scale as a Determinant of 5-Year Cumulative Costs After Ischemic Stroke: An Analysis of 11,136 Patients in Korea.

Ganesh, Aravind; Varma, Malavika

doi : 10.1212/WNL.0000000000011294

pg. 136-137

خرید پکیج و مشاهده آنلاین مقاله

Author Response: Three-Month Modified Rankin Scale as a Determinant of 5-Year Cumulative Costs After Ischemic Stroke: An Analysis of 11,136 Patients in Korea.

Kim, Seong-Eun; Lee, Juneyoung; Gorelick, Philip B.; Bae, Hee-Joon

doi : 10.1212/WNL.0000000000011295

pg. 137

خرید پکیج و مشاهده آنلاین مقاله

Association of Peri-ictal Brainstem Posturing With Seizure Severity and Breathing Compromise in Patients With Generalized Convulsive Seizures.

Vilella, Laura MD; Lacuey, Nuria MD, PhD; Hampson, Johnson P. MSBME; Zhu, Liang PhD; Omidi, Shirin MD; Ochoa-Urrea, Manuela MD; Tao, Shiqiang PhD; Rani, M.R. Sandhya PhD; Sainju, Rup K. MBBS; Friedman, Daniel MD; Nei, Maromi MD; Strohl, Kingman MD; Scott, Catherine MPhil; Allen, Luke PhD; Gehlbach, Brian K. MD; Hupp, Norma J. REEGTCLTm; Hampson, Jaison S. MD; Shafiabadi, Nassim MD; Zhao, Xiuhe MD; Reick-Mitrisin, Victoria MS; Schuele, Stephan MD, MPH; Ogren, Jennifer PhD; Harper, Ronald M. PhD; Diehl, Beate MD, PhD, FRCP; Bateman, Lisa M. MD; Devinsky, Orrin MD; Richerson, George B. MD, PhD; Ryvlin, Philippe MD, PhD; Zhang, Guo-Qiang MS, PhD; Lhatoo, Samden D. MD, FRCP

doi : 10.1212/WNL.0000000000011274

pg. e352-e365

AB Objective: To analyze the association between peri-ictal brainstem posturing semiologies with postictal generalized electroencephalographic suppression (PGES) and breathing dysfunction in generalized convulsive seizures (GCS). Methods: In this prospective, multicenter analysis of GCS, ictal brainstem semiology was classified as (1) decerebration (bilateral symmetric tonic arm extension), (2) decortication (bilateral symmetric tonic arm flexion only), (3) hemi-decerebration (unilateral tonic arm extension with contralateral flexion) and (4) absence of ictal tonic phase. Postictal posturing was also assessed. Respiration was monitored with thoracoabdominal belts, video, and pulse oximetry. Results: Two hundred ninety-five seizures (180 patients) were analyzed. Ictal decerebration was observed in 122 of 295 (41.4%), decortication in 47 of 295 (15.9%), and hemi-decerebration in 28 of 295 (9.5%) seizures. Tonic phase was absent in 98 of 295 (33.2%) seizures. Postictal posturing occurred in 18 of 295 (6.1%) seizures. PGES risk increased with ictal decerebration (odds ratio [OR] 14.79, 95% confidence interval [CI] 6.18-35.39, p < 0.001), decortication (OR 11.26, 95% CI 2.96-42.93, p < 0.001), or hemi-decerebration (OR 48.56, 95% CI 6.07-388.78, p < 0.001). Ictal decerebration was associated with longer PGES (p = 0.011). Postictal posturing was associated with postconvulsive central apnea (PCCA) (p = 0.004), longer hypoxemia (p < 0.001), and SpO2 recovery (p = 0.035). Conclusions: Ictal brainstem semiology is associated with increased PGES risk. Ictal decerebration is associated with longer PGES. Postictal posturing is associated with a 6-fold increased risk of PCCA, longer hypoxemia, and SpO2 recovery. Peri-ictal brainstem posturing may be a surrogate biomarker for GCS severity identifiable without in-hospital monitoring. Classification of Evidence: This study provides Class III evidence that peri-ictal brainstem posturing is associated with the GCS with more prolonged PGES and more severe breathing dysfunction. (C) 2021 American Academy of Neurology

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Teaching NeuroImages: Stroke With Nondecussating Corticospinal Tracts Causing Ipsilateral Weakness: Straight Forward.

Zhou, Lily W. MD; Chew, Jason MBChB, FRCPC; Field, Thalia S. MHSc, MD, FRCP

doi : 10.1212/WNL.0000000000010804

pg. e480-e481

خرید پکیج و مشاهده آنلاین مقاله